Inhibitors of poly[ADP-ribose] polymerase 1 (PARPis) show promise for treatment of
cancers which lack capacity for homologous recombination repair (HRR). However, new therapeutic strategies are required in order to overcome innate and acquired resistance to these drugs and thus expand the array of
cancers that could benefit from them. We show that human
cancer cell lines which respond poorly to
ABT-888 (a PARPi), become sensitive to it when co-treated with
vorinostat (a
histone deacetylase inhibitor (HDACi)).
Vorinostat also sensitized PARPis insensitive
cancer cell lines to
6-thioguanine (6-TG)-a
drug that targets PARPis sensitive cells. The sensitizing effect of
vorinostat was associated with increased phosphorylation of eukaryotic
initiation factor (eIF) 2α which in and of itself increases the sensitivity of
cancer cells to
ABT-888. Importantly, these
drug combinations did not affect survival of normal fibroblasts and breast cells, and significantly increased the inhibition of xenograft
tumor growth relative to each
drug alone, without affecting the mice weight or their liver and kidney function. Our results show that combination of
vorinostat and
ABT-888 could potentially prove useful for treatment of
cancer with innate resistance to PARPis due to active HRR machinery, while the combination of
vorinostat and 6-TG could potentially overcome innate or acquired resistance to PARPis due to secondary or reversal BRCA mutations, to decreased PARP-1 level or to increased expression of multiple
drug resistant
proteins. Importantly, drugs which increase phosphorylation of eIF2α may mimic the sensitizing effect of
vorinostat on cellular response to PARPis or to 6-TG, without activating all of its downstream effectors.